Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features.

Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Reemergence of Clade IIb-Associated Mpox, Germany, July-December 2023.

In July 2023, clade IIb-associated mpox reemerged in Germany at low levels, mainly affecting men who have sex with men. We report a representative case and phylogeny of available genome sequences. Our findings underscore the need for standardized surveillance and indication-based vaccination to limit transmission and help prevent endemicity.

Predicting the pathogenicity of missense variants using features derived from AlphaFold2.

MOTIVATION: Missense variants are a frequent class of variation within the coding genome, and some of them cause Mendelian diseases. Despite advances in computational prediction, classifying missense variants into pathogenic or benign remains a major challenge in the context of personalized medicine. Recently, the structure of the human proteome was derived with unprecedented accuracy using the artificial intelligence system AlphaFold2. This raises the question of whether AlphaFold2 wild-type structures can improve the accuracy of computational pathogenicity prediction for missense variants. RESULTS: To address this, we first engineered a set of features for each amino acid from these structures. We then trained a random forest to distinguish between relatively common (proxy-benign) and singleton (proxy-pathogenic) missense variants from gnomAD v3.1. This yielded a novel AlphaFold2-based pathogenicity prediction score, termed AlphScore. Important feature classes used by AlphScore are solvent accessibility, amino acid network related features, features describing the physicochemical environment, and AlphaFold2's quality parameter (predicted local distance difference test). AlphScore alone showed lower performance than existing in silico scores used for missense prediction, such as CADD or REVEL. However, when AlphScore was added to those scores, the performance increased, as measured by the approximation of deep mutational scan data, as well as the prediction of expert-curated missense variants from the ClinVar database. Overall, our data indicate that the integration of AlphaFold2-predicted structures can improve pathogenicity prediction of missense variants. AVAILABILITY AND IMPLEMENTATION: AlphScore, combinations of AlphScore with existing scores, as well as variants used for training and testing are publicly available.

De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke.

PURPOSE: RNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease. Case reports have also implicated specific variants in RNF213 with an early-onset form of moyamoya disease with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations. METHODS: Patients were identified through reanalysis of exome sequencing data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient-derived fibroblasts. RESULTS: We identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the Really Interesting New Gene (RING) domain. Individuals presented either with early-onset stroke (n = 11) or with Leigh syndrome (n = 3). No genotype-phenotype correlation could be established. Proteomics using patient-derived fibroblasts revealed no significant differences between clinical subgroups. 3D modeling revealed a clustering of missense variants in the tertiary structure of RNF213 potentially affecting zinc-binding suggesting a gain-of-function or dominant negative effect. CONCLUSION: De novo missense variants in RNF213 clustering in the E3 RING or other regions affecting zinc-binding lead to an early-onset syndrome characterized by stroke or Leigh syndrome.

Still trouble with bleeding: Risk factors for HCV transmission in men who have sex with men and behavioural trajectories from 2019 to 2021.

OBJECTIVES: To identify sexual/sex-associated risk factors for hepatitis C transmission among men who have sex with men (MSM) and visualise behavioural trajectories from 2019 to 2021. METHODS: We linked a behavioural survey to a hepatitis C cohort study (NoCo), established in 2019 across six German HIV/hepatitis C virus (HCV) treatment centres, and performed a case-control analysis. Cases were MSM with recent HCV infection, and controls were matched for HIV status (model 1) or proportions of sexual partners with HIV (model 2). We conducted conditional univariable and multivariable regression analyses. RESULTS: In all, 197 cases and 314 controls completed the baseline questionnaire and could be matched with clinical data. For regression models, we restricted cases to those with HCV diagnosed since 2018 (N = 100). Factors independently associated with case status included sex-associated rectal bleeding, shared fisting lubricant, anal douching, chemsex, intravenous and intracavernosal injections, with population-attributable fractions of 88% (model 1) and 85% (model 2). These factors remained stable over time among cases, while sexual partner numbers and group sex decreased during COVID-19 measures. CONCLUSIONS: Sexual/sex-associated practices leading to blood exposure are key factors in HCV transmission in MSM. Public health interventions should emphasize the importance of blood safety in sexual encounters. Micro-elimination efforts were temporarily aided by reduced opportunities for sexual encounters during the COVID-19 pandemic.

Recently acquired HCV infection in men who have sex with men in Germany in the direct-acting antivirals era and during the COVID-19 pandemic.

INTRODUCTION: Direct-acting antivirals (DAAs) are key to eliminating hepatitis C virus (HCV). In men who have sex with men (MSM) with HIV co-infection, recently acquired HCV infection is common. Sexual practices and reinfection rates may hamper micro-elimination despite high treatment rates. METHODS: The cohort included MSM with recently acquired HCV infection from 2014 to 2021. The patients' demographic, clinical, behavioural, and laboratory data and treatment and reinfection outcomes were documented. RESULTS: A total of 237 men with recently acquired HCV infection were included: 216 (91%) had HIV. The median age was 46 years (interquartile range [IQR] 39-52), and the median CD4 count was 660/mm3 (IQR 527-835). The annual incidence of recently acquired HCV remained between 0.28% and 0.43% but dropped to 0.02% in 2021 during the COVID pandemic, almost reaching micro-elimination. The reinfection incidence was 15.5 per 100 patient-years (95% confidence interval 12.6-18.8), and reinfection was associated with the use of crystal methamphetamine (p = 0.032) and ketamine (p = 0.042). In total, 31.3% had multiple reinfections, and four reinfections occurred in users of pre-exposure prophylaxis. CONCLUSIONS: High treatment and cure rates did not lead to HCV elimination. A change in sexual behaviour, potentially imposed by COVID-19 restrictions, led to micro-elimination in the NoCo cohort. As recently acquired HCV is prevalent in MSM with and without HIV, surveillance is necessary to consolidate elimination goals.

Incidence of sexually transmitted infections and association with behavioural factors: Time-to-event analysis of a large pre-exposure prophylaxis (PrEP) cohort.

OBJECTIVES: Our objective was to obtain long-term data on the incidence of sexually transmitted infections (STIs) and their association with behavioural factors after widespread pre-exposure prophylaxis (PrEP) implementation. METHODS: This was a time-to-event analysis of a national PrEP cohort in Switzerland (SwissPrEPared study). Participants were people without HIV interested in taking PrEP with at least two STI screening visits. Primary outcomes were incidence rate of gonorrhoea, chlamydia, and syphilis. The association between behavioural factors and STI diagnosis was expressed using hazard ratios. We adjusted for testing frequency and calendar year. RESULTS: This analysis included 3907 participants enrolled between April 2019 and April 2022, yielding 3815.7 person-years of follow-up for gonorrhoea (15 134 screenings), 3802.5 for chlamydia (15 141 screenings), and 3858.6 for syphilis (15 001 screenings). The median age was 39 years (interquartile range [IQR] 32-47), 93.8% (n = 3664) identified as men who have sex with men (MSM). The incidence was 22.8 (95% confidence interval [CI] 21.3-24.4) per 100 person-years for gonorrhoea, 26.3 (95% CI 24.7-28.0) for chlamydia, and 4.4 (95% CI 3.8-5.1) for syphilis. Yearly incidence rates decreased between 2019 (all bacterial STIs: 81.6; 95% CI 59.1-109.9) and 2022 (all bacterial STIs: 49.8; 95% CI 44.6-55.3). Participants reporting chemsex substance use were at higher risk of incident STIs, as were those reporting multiple sexual partners. Younger age was associated with a higher risk of gonorrhoea and chlamydia. CONCLUSIONS: Incidence rates of bacterial STIs decreased over time. Young MSM, those with multiple partners, and those using chemsex substances were at increased risk of STIs.

Drought increases Norway spruce susceptibility to the Eurasian spruce bark beetle and its associated fungi.

Drought affects the complex interactions between Norway spruce, the bark beetle Ips typographus and associated microorganisms. We investigated the interplay of tree water status, defense and carbohydrate reserves with the incidence of bark beetle attack and infection of associated fungi in mature spruce trees. We installed roofs to induce a 2-yr moderate drought in a managed spruce stand to examine a maximum of 10 roof and 10 control trees for resin flow (RF), predawn twig water potentials, terpene, phenolic and carbohydrate bark concentrations, and bark beetle borings in field bioassays before and after inoculation with Endoconidiophora polonica and Grosmannia penicillata. Drought-stressed trees showed more attacks and significantly longer fungal lesions than controls, but maintained terpene resin defenses at predrought levels. Reduced RF and lower mono- and diterpene, but not phenolic concentrations were linked with increased host selection. Bark beetle attack and fungi stimulated chemical defenses, yet G. penicillata reduced phenolic and carbohydrate contents. Chemical defenses did not decrease under mild, prolonged drought in our simulated small-scale biotic infestations. However, during natural mass attacks, reductions in carbon fixation under drought, in combination with fungal consumption of carbohydrates, may deplete tree defenses and facilitate colonization by I. typographus.

HDR, the last enzyme in the MEP pathway, differently regulates isoprenoid biosynthesis in two woody plants.

Dimethylallyl diphosphate (DMADP) and isopentenyl diphosphate (IDP) serves as the universal C5 precursors of isoprenoid biosynthesis in plants. These compounds are formed by the last step of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, catalyzed by (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate reductase (HDR). In this study, we investigated the major HDR isoforms of two woody plant species, Norway spruce (Picea abies) and gray poplar (Populus × canescens), to determine how they regulate isoprenoid formation. Since each of these species has a distinct profile of isoprenoid compounds, they may require different proportions of DMADP and IDP with proportionally more IDP being needed to make larger isoprenoids. Norway spruce contained two major HDR isoforms differing in their occurrence and biochemical characteristics. PaHDR1 produced relatively more IDP than PaHDR2 and it encoding gene was expressed constitutively in leaves, likely serving to form substrate for production of carotenoids, chlorophylls, and other primary isoprenoids derived from a C20 precursor. On the other hand, Norway spruce PaHDR2 produced relatively more DMADP than PaHDR1 and its encoding gene was expressed in leaves, stems, and roots, both constitutively and after induction with the defense hormone methyl jasmonate. This second HDR enzyme likely forms a substrate for the specialized monoterpene (C10), sesquiterpene (C15), and diterpene (C20) metabolites of spruce oleoresin. Gray poplar contained only one dominant isoform (named PcHDR2) that produced relatively more DMADP and the gene of which was expressed in all organs. In leaves, where the requirement for IDP is high to make the major carotenoid and chlorophyll isoprenoids derived from C20 precursors, excess DMADP may accumulate, which could explain the high rate of isoprene (C5) emission. Our results provide new insights into the biosynthesis of isoprenoids in woody plants under conditions of differentially regulated biosynthesis of the precursors IDP and DMADP.

Specific decorations of 17-hydroxygeranyllinalool diterpene glycosides solve the autotoxicity problem of chemical defense in Nicotiana attenuata.

The native diploid tobacco Nicotiana attenuata produces abundant, potent anti-herbivore defense metabolites known as 17-hydroxygeranyllinalool diterpene glycosides (HGL-DTGs) whose glycosylation and malonylation biosynthetic steps are regulated by jasmonate signaling. To characterize the biosynthetic pathway of HGL-DTGs, we conducted a genome-wide analysis of uridine diphosphate glycosyltransferases (UGTs) and identified 107 family-1 UGT members. The transcript levels of three UGTs were highly correlated with the transcript levels two key HGL-DTG biosynthetic genes: geranylgeranyl diphosphate synthase (NaGGPPS) and geranyllinalool synthase (NaGLS). NaGLS's role in HGL-DTG biosynthesis was confirmed by virus-induced gene silencing. Silencing the Uridine diphosphate (UDP)-rhamnosyltransferase gene UGT91T1 demonstrated its role in the rhamnosylation of HGL-DTGs. In vitro enzyme assays revealed that UGT74P3 and UGT74P4 use UDP-glucose for the glucosylation of 17-hydroxygeranyllinalool (17-HGL) to lyciumoside I. Plants with stable silencing of UGT74P3 and UGT74P5 were severely developmentally deformed, pointing to a phytotoxic effect of the aglycone. The application of synthetic 17-HGL and silencing of the UGTs in HGL-DTG-free plants confirmed this phytotoxic effect. Feeding assays with tobacco hornworm (Manduca sexta) larvae revealed the defensive functions of the glucosylation and rhamnosylation steps in HGL-DTG biosynthesis. Glucosylation of 17-HGL is therefore a critical step that contributes to the resulting metabolites' defensive function and solves the autotoxicity problem of this potent chemical defense.

HIV Testing and Treatment among HIV-Positive Men who have Sex with Men (MSM) Living in Russia: Data from Two Waves of the European MSM Internet Survey.

We examined changes in HIV testing and medical care among men who have sex with men (MSM) in Russia. Data come from the 2010 and 2017 waves of the European MSM Internet Survey. From 2010 to 2017 there was an increase in the proportion who had ever received an HIV test (+ 11.2%), had tested for HIV in the last year (+ 2.1%), had ever taken antiretroviral therapy (ART) (+ 31.9), were currently taking ART (+ 31.5%), and had an undetectable viral load (+ 19.4%). These results are encouraging, yet they also reveal that substantial proportions of MSM experience considerable unmet prevention and treatment needs.

RESUMEN: Examinamos los cambios en las pruebas de detección de VIH y la atención médica entre hombres que tienen sexo con hombres (HSH) en Rusia. Los datos provienen de las olas de 2010 y 2017 de la Encuesta Europea de Internet para HSH. De 2010 a 2017 hubo un aumento en la proporción de quienes alguna vez se habían hecho una prueba de VIH (+ 11.2%), se habían hecho una prueba de VIH en el último año (+ 2.1%), alguna vez habían tomado terapia antirretroviral (TAR) (+ 31.9%), estaban tomando TAR actualmente (+ 31.5%) y tenían una carga viral indetectable (+ 19.4%). Estos resultados son alentadores, pero también revelan que una proporción sustancial de HSH experimenta considerables necesidades de prevención y tratamiento no satisfechas.

Determinants of HIV Testing Among Migrant Men Who Have Sex With Men from Sub-Saharan Africa and Other Regions Residing in 10 European Countries.

Migrant men who have sex with men (mMSM) from sub-Saharan Africa (SSA) and other regions outside Europe are highly vulnerable to HIV. However, research on the determinants of HIV testing among mMSM from SSA, and how these differ across the categories of mMSM living in Europe, is limited. Using data from the European MSM Internet Survey (EMIS-2017), we assessed HIV testing prevalence and recency in mMSM from SSA and other mMSM residing in ten European countries, as well as the determinants of HIV testing across different mMSM categories with logistic regression analyses. Ever-testing for HIV was slightly higher in mMSM from SSA (83%) compared to other mMSM categories (75-80%), except for mMSM from Latin America and Caribbean region (84%). Overall, 20% of mMSM had never tested. In multivariable analysis, higher age (adjusted odds ratio [AOR] 1.05, 95% confidence interval [CI] 1.01-1.10), higher HIV knowledge (AOR 1.45, 95%-CI 1.11-1.90), and residence in smaller settlements (AOR 0.45, 95%-CI 0.21-0.96) were significantly associated with ever testing for HIV in mMSM from SSA. Comparing mMSM from SSA to mMSM from other regions, we found varying significant similarities (higher age, residence in smaller settlements and HIV knowledge) and differences (lower educational attainment, not identifying as gay, being a student, and limited disclosure of homosexual attraction) in the determinants of ever-testing for HIV. Community-specific interventions addressing identified sociodemographic and behavioral determinants to increase HIV testing uptake in the different mMSM categories and better data for further research are warranted.

When awareness is not a barrier to PrEP uptake among men who have sex with men who are eligible for PrEP in France.

Despite PrEP being available and free of charge in France, a gap remains between the estimated number of men who have sex with men (MSM) with high-risk exposure to HIV and the number of MSM PrEP users. The objective of this study is to identify factors associated with non-intention to use PrEP among PrEP-eligible and PrEP-aware MSM in France, "non-intenders".European MSM Internet Survey (EMIS)-2017 was a cross-sectional survey conducted among MSM concerning their HIV prevention needs. Logistic regression models were used to identify factors associated with "non-intenders".Compared to PrEP users, factors associated with non-intention to use PrEP were: age (aOR[95%CI] = 3.80[2.21;6.53]); not being vaccinated against hepatitis B (2.20[1.45;3.34]); self-efficacy (1.84[1.29;2.60]); lower knowledge about on-demand PrEP (11.48[7.37;17.87]) and daily PrEP (2.58[1.27;5.25]); not having a PrEP discussion at a hospital (12.39[8.90;17.27]) or at a community service/drop-in (4.93[3.48;6.97]); living in a department with few PrEP access points (1.70[1.10;2.63]).On-demand PrEP may meet the prevention needs of "non-intenders" who have lower HIV risk perception. Increasing communication from health providers and community health workers to all MSM is needed.

Exploring group differences in the response to a sexual risk reduction intervention to prevent hepatitis C virus reinfection in HIV-infected MSM: a mixed-methods study.

To prevent hepatitis C virus (HCV) reinfection, within the Swiss HCVree Trial, a preventive risk reduction intervention was implemented alongside curative treatment. Formative qualitative research identified three response patterns to the intervention. This mixed-methods study's aim was to cross-validate group differences in (a) the content of sexual risk reduction goals set during intervention and (b) the extent of their behavioural change in condomless anal intercourse with non-steady partners (nsCAI), sexualised and intravenous drug use at start and six-month post-intervention. Qualitative thematic analysis was used to summarise goal setting domains. Quantitative descriptive analysis was used to evaluate group differences based on assumptions of the group descriptions. Results largely confirmed assumptions on inter-group response differences in goal setting and behaviour: as expected group 1 Avoid risks showed the lowest HCV risk profile with changes in nsCAI. Group 2 Minimize-risks and Group 3 Accept-risks showed unchanged nsCAI. Group 3 had the highest HCV risk profile. Differences in their goal preferences (1: condom use; 2 reduction blood exposure; 3 safer dating) highlight diversity in attitudes to behavioural change. Our results improve understanding of variability in intervention responses such as changes in attitudes and behaviour. This provides evidence for intervention tailoring and outcome measurement.

Clinically inapparent mpox virus (MPXV) infections among clients of three anonymous Community Based Voluntary Counselling and Testing centres in Berlin, Germany, 2022-2023.

INTRODUCTION: Since the mpox outbreak in 2022, it was unclear if and how often infections with mpox virus (MPXV) were clinically inapparent, i.e. not presenting to clinical care with mpox symptoms. Moreover, it was hypothesized that MPXV circulated in the affected communities before the outbreak was officially detected. METHODS: We retrospectively tested rectal and urethral swabs, and pooled samples for presence of MPXV. Samples were obtained from routine STI testing of three anonymous Community Based Voluntary Counselling and Testing (CBVCT) centres in Berlin, in 2022 and 2023. Testing results were linked to anonymously provided behavioural data. RESULTS: Overall, 9,053 samples from 6,600 client visits were included. Clinically inapparent MPXV infections were detectable in 1.1% of the samples. We did not find MPXV infections in the month before the first cases appeared in Berlin or between October 2022 and January 2023 when case numbers were low in Germany. However, during the outbreak period in 2022, we found clinically inapparent MPXV infections among 2.2% of the clients and during summer/autumn 2023 among 0.3%. The number of condomless anal/vaginal intercourse partners within the previous 6 months and PrEP use were identified as predictors of clinically inapparent MPXV infection. CONCLUSION: Clinically inapparent MPXV infections occurred during the mpox outbreak in Berlin in 2022 and post-outbreak in summer/autumn 2023. Unrecognized MPXV circulation in Berlin before the recognition of the outbreak in May 2022 appears unlikely. However, low-level sustained circulation of clinically inapparent MPXV infections need to be acknowledged in mpox prevention strategies.

Sex work, syndemic conditions and condomless anal intercourse among men who have sex with men who engage in sex work in Latin America.

Background In Latin American countries and Suriname, sexual transmission is one of the most common modes of HIV transmission, and men who have sex with men (MSM) who engage in sex work constitute a key population. Methods In a sample of MSM (N =53,166) from the Latin American Internet Survey (2018) across 18 countries, we examined how sex work engagement is associated with syndemic conditions (multidrug use, homophobic abuse, depression/anxiety, alcohol dependency (CAGE alcohol questionnaire) and internalised homonegativity) and condomless anal intercourse with non-steady male partners using separate logistic regressions. We then used a structural equation model to determine if and how syndemic conditions mediate the relationship between sex work engagement and non-steady male partners. Results We found that getting paid for sex was associated with less condom use for anal intercourse with non-steady male partners and particular syndemic conditions, such as multidrug use, homophobic abuse and alcohol dependency. In our structural equation model, the results showed that the direct relationship between sex work engagement and non-steady male partners was positive and significant, and syndemic conditions partially mediated this relationship. Conclusion Our results highlight the continuing need for including MSM who engage in sex work and those who experience syndemic conditions in the prevention strategies targeted to MSM in Latin America and Suriname, to prevent the transmission of HIV.

Ten-year minimal follow-up of lateral opening wedge distal femoral osteotomy for lateral femorotibial osteoarthritis: Good survivorship and high patient satisfaction.

PURPOSE: This study aimed (1) to determine complications and survival rates of lateral opening wedge distal femoral osteotomy (LOW-DFO) in the long term, (2) to assess their clinical outcomes in the long term and (3) to identify risk factors of failure. METHODS: Between 1991 and 2011, 62 LOW-DFOs were performed in the same department. Inclusion criteria were all isolated LOW-DFO performed for isolated lateral tibiofemoral osteoarthritis and valgus malalignment, with a minimum 10-year follow-up. Thirty-eight patients were included, with a mean age of 48 ± 9 years. All patients had clinical and radiological assessments. The survival curves were calculated based on the following endpoints: unicompartmental or total knee arthroplasty. RESULTS: The mean follow-up was 15.2 ± 4.4 [10-29] years. The mean preoperative mechanical FemoroTibial Axis (mFTA) was 188.8° ± 3.2° [184°-197°], primarily due to femur deformity (mean lateral distal femoral axis [LDFA] 83.2° ± 2.8°). Bone union was achieved in 89.5% of patients (n = 34) at a mean delay of 6.5 ± 6.7 months. The complication rate was 26% (five stiffness, one nonunion, three secondary displacements and one deep vein thrombosis). Nine revision surgeries (24%) were recorded. Survival rates at 5 and 10 years were 92.1% and 78.9%, respectively. The mean delay between DFO and total knee arthroplasty (TKA) was 11.6 ± 5.7 [1-27] years. Nineteen patients (50%) were free of TKA at the last follow-up. KSS scores were improved significantly. Return to sports was obtained in 92% of cases (n = 35), with a mean delay of 11 ± 8 months. Seventy-four per cent of patients were satisfied or very satisfied with the surgery. Eighty-four per cent would be willing to undergo the surgery again. Older age (p = 0.032) was a significant risk factor for TKA conversion. CONCLUSION: LOW-DFO is an efficient procedure to manage lateral knee osteoarthritis in young patients with valgus deformity, with a good survival rate at 10 years and high patient satisfaction. LEVEL OF EVIDENCE: Level III.

Bacteriophage therapy as an innovative strategy for the treatment of Periprosthetic Joint Infection: a systematic review.

BACKGROUND: Periprosthetic Joint Infection (PJI) following hip and knee arthroplasty is a catastrophic complication in orthopaedic surgery. It has long been a key focus for orthopaedic surgeons in terms of prevention and management. With the increasing incidence of antibiotic resistance in recent years, finding more targeted treatment methods has become an increasingly urgent issue. Bacteriophage Therapy (BT) has emerged as a promising adjunctive treatment for bone and joint infections in recent years. It not only effectively kills bacteria but also demonstrates significant anti-biofilm activity, garnering substantial clinical interest due to its demonstrated efficacy and relatively low incidence of adverse effects. PURPOSE: This review aims to systematically evaluate the efficacy and safety of bacteriophage therapy in treating PJI following hip and knee arthroplasty, providing additional reference for its future clinical application. METHODS: Following predefined inclusion and exclusion criteria, our team conducted a systematic literature search across seven databases (PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, CNKI, and WanFang Database). The search was conducted up to May 2024 and included multiple clinical studies on the use of bacteriophage therapy for treating PJI after hip and knee arthroplasty to assess its efficacy and safety. RESULTS: This systematic review included 16 clinical studies after screening, consisting of 15 case reports and one prospective controlled clinical trial, involving a total of 42 patients with PJI treated with bacteriophage therapy. The average patient age was 62.86 years, and 43 joints were treated, with patients undergoing an average of 5.25 surgeries. The most common pathogen in these infections was Staphylococcus aureus, accounting for 18 cases. 33 patients received cocktail therapy, while nine were treated with a single bacteriophage preparation. Additionally, all patients underwent suppressive antibiotic therapy (SAT) postoperatively. All patients were followed up for an average of 13.55 months. There were two cases of recurrence, one of which resulted in amputation one year postoperatively. The remaining patients showed good recovery outcomes. Overall, the results from the included studies indicate that bacteriophage therapy effectively eradicates infectious strains in various cases of PJI, with minimal side effects, demonstrating promising clinical efficacy. CONCLUSION: In the treatment of PJI following hip and knee arthroplasty, bacteriophages, whether used alone or in combination as cocktail therapy, have shown therapeutic potential. However, thorough preoperative evaluation is essential, and appropriate bacteriophage types and treatment regimens must be selected based on bacteriological evidence. Future large-scale, randomized controlled, and prospective trials are necessary to validate the efficacy and safety of this therapy.

Deoxyxylulose 5-Phosphate Synthase Does Not Play a Major Role in Regulating the Methylerythritol 4-Phosphate Pathway in Poplar.

The plastidic 2-C-methylerythritol 4-phosphate (MEP) pathway supplies the precursors of a large variety of essential plant isoprenoids, but its regulation is still not well understood. Using metabolic control analysis (MCA), we examined the first enzyme of this pathway, 1-deoxyxylulose 5-phosphate synthase (DXS), in multiple grey poplar (Populus × canescens) lines modified in their DXS activity. Single leaves were dynamically labeled with 13CO2 in an illuminated, climate-controlled gas exchange cuvette coupled to a proton transfer reaction mass spectrometer, and the carbon flux through the MEP pathway was calculated. Carbon was rapidly assimilated into MEP pathway intermediates and labeled both the isoprene released and the IDP+DMADP pool by up to 90%. DXS activity was increased by 25% in lines overexpressing the DXS gene and reduced by 50% in RNA interference lines, while the carbon flux in the MEP pathway was 25-35% greater in overexpressing lines and unchanged in RNA interference lines. Isoprene emission was also not altered in these different genetic backgrounds. By correlating absolute flux to DXS activity under different conditions of light and temperature, the flux control coefficient was found to be low. Among isoprenoid end products, isoprene itself was unchanged in DXS transgenic lines, but the levels of the chlorophylls and most carotenoids measured were 20-30% less in RNA interference lines than in overexpression lines. Our data thus demonstrate that DXS in the isoprene-emitting grey poplar plays only a minor part in controlling flux through the MEP pathway.